The long term objectives of this project are to clarify interactions among HIV-1, human leukocytes, and immune responsiveness, with the goal of utilizing this information to prevent the pathogenic consequences of infection, i.e. the development of AIDS. The specific aims for this project period are to develop new strategies for the use of combination therapy for HIV-1 infection, determine the mechanisms for drug failure after prolonged therapy, describe the evolution of HIV-1 phenotypes and genotypes during various forms of therapy, and characterize the effects of antiviral treatments on HIV-1 specific cytotoxic T lymphocyte (CTL) reactivity. Experiments will be conducted both on infected cells in culture as well as on specimens derived from infected patients. Combination and sequential treatment regimens will be employed involving nucleosides (ddi, AZT, ddc) as well as other agents (rIFN alpha A, protease inhibitors, non-nucleoside reverse transcriptase inhibitors). Breakthrough viruses during therapy will be evaluated for genotypic alterations and phenotypic characteristics (e.g., syncytium capacity, cell tropism). Cells from prolonged treatment regimens will be evaluated for refractoriness to the drug in question. Molecular interactions among drugs in combination will be explored. CTL activity will be prospectively measured in patients on therapy, and the effects of drugs or drug combinations on CTL activity will be examined. These studies should help form the basis for more rational anti-HIV-1 combination therapy in future years.